Pseudomonas aeruginosa produces the bacterial exotoxin Pseudomonas exotoxin A. The exotoxin consists of four structural domains, namely Ia, II, Ib and III. When domain Ia is cleaved off the exotoxin, the resulting protein is known as PE.sub.40. Transforming growth factor alpha (TGF.alpha.) is a protein that can be genetically fused to the amino terminus of PE.sub.40 to produce the chimeric protein TGF.alpha.PE.sub.40. When cysteine residues in domain II of PE.sub.40 are deleted or substituted by non-cysteinyl amino acids, the resulting protein is PE.sub.40 ab, which when genetically fused to TGF.alpha. produces TGF.alpha.PE.sub.40 ab.
TGF.alpha.PE.sub.40 ab is potentially useful in treating human bladder cancer, being toxic to bladder cancer cells The TGF.alpha. end of the protein binds to Epidermal Growth Factor receptors (EGFr) that are expressed at the surface of bladder cancer cells at elevated levels relative to normal bladder cells. Administration of TGF.alpha.PE.sub.40 ab to a patient is via the intravesicular route. A solution of the drug is administered via a urethral catheter into the bladder, where the solution is allowed to dwell for a period of time, most preferably about two hours. During this period of residence in the bladder, the drug solution would ordinarily be subjected to an acidic environment as the normal pH range of human urine is 5 to 8, depending on the patient's diet and the time of day. Moreover, urine itself has a high buffering capacity. Since it is now known that TGF.alpha.PE.sub.40 ab is pH-sensitive in its binding to its receptor site as well as in its conformation, the optimum pH range for its action in the bladder had to be determined, and a formulation compounded that would maintain that optimum pH range and buffer it against pH changes in the bladder. Maximal binding of TGF.alpha.PE.sub.40 ab to the EGF receptor was thus found to occur above a pH of 6.5. Moreover, TGF.alpha.PE.sub.40 ab was found to form an aggregate at an approximate pH range of 5.5 or below. The present invention solves these buffering problems by providing for a buffering diluent that buffers a solution of TGF.alpha.PE.sub.40 ab prior to intravesicular administration so as to overwhelm natural urinary buffering capacity and maintain a desired pH range of 6.5-7.8 in the human bladder during therapy.